DESCRIPTION: The repeated administration of psychostimulant drugs, such as amphetamine or cocaine, produces persistent behavioral and neurobiological adaptations that are thought to contribute to the long-term sequelae associated with drug abuse, including tolerance, sensitization, dependence and addiction. One form of neurobehavioral adaptation implicated in addiction is represented by the phenomenon of behavioral sensitization, whereby past drug exposure renders individuals hypersensitive to the psychomotor activating and incentive motivational effects of drugs. The overall aim of this application is to better understand the long-term neurobiological consequences of repeated exposure to psychostimulant drugs, the role these play in the development of behavioral sensitization, and their implications for addiction. More specifically, we have recently found that repeated treatment with amphetamine or cocaine produces persistent changes in the structure of dendrites and dendritic spines on neurons in the nucleus accumbens and prefrontal cortex, two brain regions prominently implicated in mediating drug reward. These findings suggest that exposure to psychostimulant drugs alters patterns of synaptic connectivity in these brain regions, presumably also altering the function of this neural circuitry. A specific aim of this application is to further characterize the ability of psychostimulant drugs to alter neural circuitry in brain reward regions (using the Golgi technique) and to determine whether these structural adaptations are related to the development of psychomotor sensitization. In one series of experiments we will use a variety of procedures known to increase or decrease the strength or persistence of behavioral sensitization to accumulate converging evidence regarding the extent to which structural adaptations co-vary with the behavioral phenomenon. In other experiments we will acquire more detailed information about the exact locus of psychostimulant drug-induced changes in spine density on medium spiny neurons and pyramidal cells (i.e., are structural changes confined to one portion of the dendritic tree), and whether other cell populations are also affected. In addition, we will determine whether drug self-administration experience produces effects on dendritic structure similar to those seen with experimenter-administered drug, and the relationship between the degree of exposure to self-administered cocaine, escalation of intake and morphological adaptations. Finally, in the last year of the award period we will expand the scope of our investigations to study the implications of drug-induced plasticity for other forms of experience-dependent plasticity. Specifically, we will test whether exposure to psychostimulant drugs at one point in life limits the ability of the affected brain regions to undergo structural adaptations later in life, as a consequence of changes in environmental condition or in association with recovery from brain damage.